Factors related to lymph node sampling at the time of surgery in children, adolescents, and young adults with unilateral non-metastatic renal cell carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC) is rare in the pediatric, adolescent, and young adult (PAYA) population. PAYA patients with RCC have a high rate of lymph node (LN) involvement, regardless of primary tumor size, yet data to guide surgical LN management in this group are limited. OBJECTIVE: The objective of this study was to determine what factors are associated with LN sampling (protocol adherence) in PAYAs with RCC. METHODS: The National Cancer Database (NCDB) between 2004 and 2013 was queried for patients aged ≤30 yrs with non-metastatic, unilateral RCC managed with surgery. Logistic regression analyses were performed to evaluate factors associated with LN sampling. RESULTS: A total of 2857 patients met study criteria. Pathologically, 2510 (87.8%) patients were Nx, 278 (9.7%) N0, and 69 (2.4%) N1. Older age was associated with omission of LN sampling (odds ration [OR]: 1.065, 95% confidence interval [CI]: 1.04-1.1, P < 0.001). Higher institutional volume (OR: 0.971, 95% CI: 0.96-0.99, P < 0.001), stage 3 tumors (OR: 0.19, 95% CI: 0.11-0.33, P < 0.001), pre-operative clinical node involvement (OR: 0.32, 95% CI: 0.12-0.86, P = 0.024), tumor size >10 cm (OR: 0.27, 95% CI: 0.12-0.57, P = 0.001), and radical nephrectomy (OR: 0.245, 95% CI: 0.16-0.38, P < 0.001) were associated with patients undergoing LN sampling. DISCUSSION: Lymph node sampling is performed in <15% of PAYA patients with RCC. Given the higher rate of translocation RCC pathology in younger patients, which leads to a higher prevalence of nodal involvement (especially with small masses), and the subsequent need for aggressive surgical control of disease, LN sampling and protocol adherence are potentially underutilized in this population and may present a unique opportunity for urologists to improve the care of PAYAs. Data from administrative databases are helpful for rare diseases such as PAYA RCC, but comes with limitations such as missing data. There are several factors that could contribute to LN sampling utilization (National comprehensive cancer network (NCCN) or Children's Oncology Group institution designation, surgeon experience, annual volume, specialty, operative approach, etc.) that cannot be further examined using the NCDB. CONCLUSION: Pediatric, adolescent, and young adult patients with localized RCC are less likely to undergo surgical LN sampling if they are older, have tumors <10 cm or of less advanced stage, have no pre-operative clinical suspicion of LN involvement, are treated with partial nephrectomy, or are treated at lower volume centers. It appears that approaches from adults with RCC are being applied to PAYAs despite evidence that PAYAs with RCC experience a significant rate of LN involvement even with small tumors.

Appropriateness for testis-sparing surgery based on the testicular tumor size in a pediatric and adolescent population.

INTRODUCTION: In children, most small testicular tumors are benign, and testicular-sparing surgery (TSS) is a viable treatment option. OBJECTIVE: The objective of this study is to assess for correlation between the tumor size and final pathologic diagnoses appropriate for TSS for pediatric and adolescent patients with an intratesticular mass and negative serum tumor markers (STMs). MATERIALS AND METHODS: A retrospective review of 24 patients (aged 0-18 years) who underwent radical or partial orchiectomy between 2003 and 2015. Patients with unifocal, unilateral intratesticular tumors and negative STMs were included. Tumors with benign and non-germ cell histology were considered appropriate for TSS, and active germ cell tumor elements on final histology were categorized as inappropriate for TSS. Baseline characteristics, tumor size, and frozen section results were evaluated for association, for the entire cohort and then for a subset of pubertal and postpubertal patients (defined as ≥10 years old). RESULTS: Patients with testicular tumor pathology inappropriate for TSS were significantly older (median age 17.1 years, P = 0.03). A 2-cm size cutoff did not accurately predict pathology for the entire cohort, or for just pubertal and postpubertal patients (P = 0.132, P = 0.154, respectively). Frozen section and final pathology demonstrated good agreement (κ = 0.826, P < 0.001) as did pre-operative and final pathologic size measurement (κ = 0.703, P < 0.001). Frozen section analysis did not miss a TSS inappropriate pathology. DISCUSSION: The present data refute the finding in adults that a 2-cm cutoff accurately predicts pathology in pediatric patients with an intratesticular mass and normal STMs. These data suggest that TSS should still be offered, regardless of the tumor size alone, but frozen section appears to more accurately predict pathology than the tumor size, and its use should, thus, be emphasized. There are several limitations of this study to mention. First, this is a retrospective review of a small cohort of patients with a rare clinical scenario, which necessitated the combination of pediatric and adolescent patients. The study did not evaluate oncologic outcomes. CONCLUSIONS: In children with an intratesticular tumor and normal STMs, a tumor size cutoff of 2 cm does not appear to accurately predict the final pathology. However, the data presented support the continued use intra-operative frozen section analysis in both children and adolescents undergoing TSS.

Development of a postoperative care pathway for children with renal tumors.

PURPOSE: To identify the factors associated with a shorter postoperative stay, as an initial step to develop a care pathway for children undergoing extirpative kidney surgery. STUDY DESIGN: This study retrospectively reviewed patients managed with upfront open radical nephrectomy for renal tumors between 2005 and 2016 at a pediatric tertiary care facility. Univariate and multivariate logistic regression were performed to identify factors associated with early discharge (by postoperative day 4). RESULTS: A total of 84 patients met inclusion criteria. Median age was 28.1 months (range 1.8-193.1). Thirty-four (40.5%) patients had a nasogastric tube postoperatively. The patients were advanced to a clear liquid diet on a median postoperative day 2 (range 0-7) and regular diet on a median postoperative day 3 (range 1-8). Median time from surgery to discharge was 5 days (range 2-12), with 38 (45.2%) discharged early. Univariate and multivariate logistic regression analyses showed that earlier resumption of regular diet (OR 0.523, P = 0.028) was positively associated with early discharge. Other analyzed factors were not significant (see Table). DISCUSSION: Timely initiation of adjuvant therapy is a specific requirement of Children's Oncology Group (COG) protocols. Chemotherapy and radiation therapy are ideally initiated simultaneously, as early as possible, within 2 weeks of surgery. Thus, factors that can facilitate early discharge from the hospital can maximize protocol adherence with respect to timing of adjuvant therapy initiation and optimize patient outcome. This study shed light on several postoperative factors and how these relate to postoperative stay and recovery. Specifically, tumor size, pre-operative bowel preparation, extent of lymph node sampling, stage, operative time, estimated blood loss, surgical service, postoperative nasogastric tube use, transfusion, and chemotherapy prior to discharge were not associated with discharge timing. Early re-feeding was associated with early discharge. Thus, it seems reasonable that, when developing a postoperative care pathway for these patients, these factors be considered and specifically encourage early re-feeding. In pediatrics, data on early recovery after surgery protocols are limited, and high-quality studies are unavailable. Within pediatric urology, early recovery after surgery protocols in children undergoing major urologic reconstruction have been shown to reduce hospital stay and can decrease complication rates. It seems reasonable that a similar pathway can be applied to children undergoing radical nephrectomy for suspected malignancy. CONCLUSIONS: For children with renal tumors who underwent radical nephrectomy, early re-feeding was associated with a shorter time to discharge. Use of bowel preparation and nasogastric tube did not appear to shorten time to discharge. These data are important for developing postoperative care pathways for these patients.

Prospective study of enhanced recovery after surgery protocol in children undergoing reconstructive operations.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocol is a set of peri-operative strategies to increase speed of recovery. ERAS is well established in adults but has not been well studied in children. OBJECTIVE: The purpose of the current study was to establish the safety and efficacy of an ERAS protocol in pediatric urology patients undergoing reconstructive operations. It was hypothesized that ERAS would reduce length of stay and decrease complications when compared with historical controls. STUDY DESIGN: Institutional Review Board approval was obtained to prospectively enroll patients aged <18 years if they had undergone urologic reconstruction that included a bowel anastomosis. ERAS included: no bowel preparation, administration of pre-operative oral carbohydrate liquid, avoidance of opioids, regional anesthesia, laparoscopy when feasible, no postoperative nasogastric tube, early feeding, and early removal of intravenous fluids (IVF). Recent (2009-2014) historical controls were propensity matched in a 2:1 ratio on age, sex, ventriculoperitoneal shunt status and whether the patient was undergoing bladder augmentation. Outcomes were protocol adherence, length of stay (LOS), emergency department (ED) visits, re-admission within 30 days, re-operations and adverse events occurring within 90 days of surgery. RESULTS: A total of 26 historical and 13 ERAS patients were included. Median ages were 10.4 (IQR 8.0-12.4) and 9.9 years (IQR 9.1-11), respectively (P = 0.94) (see Summary Table). There were no significant between-group differences in prior abdominal surgery (38% vs 62%), rate of augmentation (88% vs 92%) or primary diagnosis of spina bifida (both 62%). ERAS significantly improved use of pre-operative liquid load (P < 0.001), avoidance of opioids (P = 0.046), early discontinuation of IVF (P < 0.001), and early feeding (P < 0.001). Protocol adherence improved from 8/16 (IQR 4-9) historically to 12/16 (IQR 11-12) after implementation of ERAS. LOS decreased from 8 days to 5.7 days (P = 0.520). Complications of any grade per patient decreased from 2.1 to 1.3 (OR 0.71, 95% CI 0.51-0.97). There were fewer complications per patient across all grades with ERAS. No differences were seen in emergency department (ED) visits, re-admissions and re-operations. DISCUSSION: Implementation improved consistency of care delivered. Tenets of ERAS that appeared to drive improvements included maintenance of euvolemia through avoidance of excess fluids, multimodal analgesia, and early feeding. CONCLUSION: ERAS decreased length of stay and 90-day complications after pediatric reconstructive surgery without increased re-admissions, re-operations or ED visits. A multicenter study will be required to confirm the potential benefits of adopting ERAS.

Patterns of lymph node sampling and the impact of lymph node density in favorable histology Wilms tumor: An analysis of the national cancer database.

INTRODUCTION: There is controversy about the role of lymph node (LN) sampling or dissection in the management of favorable histology (FH) Wilms tumor (WT), specifically how it performed and how it may impact survival. OBJECTIVE: The objective of this study was to analyze factors affecting LN sampling patterns and the impact of LN yield and density (number of positive LNs/LNs examined) on overall survival (OS) in patients with advanced-stage favorable histology Wilms tumor (FHWT). METHODS: The National Cancer Database (NCDB) was queried for patients with FHWT during 2004-2013. Demographic, clinical and OS data were abstracted for those who underwent surgical resection. Poisson regression was performed to analyze how factors influenced LN yield. Patients with positive LNs had LN density calculated and were further analyzed. RESULTS: A total of 2340 patients met criteria, with a median age at diagnosis of 3 years (range 0-78 years). The median number of LNs examined was three (range 0-87). Lymph node yield was affected by age, race, insurance, tumor size, laterality, advanced stage, LN positivity, and institutional volume. A total of 390 (16.6%) patients had LN-positive disease. Median LN density for these LN-positive patients was 0.38 (range 0.02-1) (Summary Figure). Estimated 5-year OS was significantly improved for those with LN density ≤0.38 vs. >0.38 (94% vs. 84.6%, P = 0.012). In this population, on multivariate analysis, age and LN density were significant predictors of OS. DISCUSSION: It is difficult to compile large numbers of cases in rare diseases like WT, and fortunately a large administrative database such as the NCDB can serve as a great resource. However, administrative data come with inherent limitations such as missing data and inability to account for a variety of factors that may influence LN yield and/or OS (specimen designation, pathologist experience, surgeon experience/volume, institutional Children's Oncology Group (COG) association, etc.). In this specific disease, the American Joint Committee on Cancer staging (captured by the NCDB) is different than the COG WT staging system that is used clinically, and the NCDB does not capture oncologic outcomes beyond OS. CONCLUSIONS: In a review of the NCDB, various factors associated with LN yield and observed LN density were identified to be significantly associated with OS in patients with LN-positive FHWT. This reinforces the need for adequate LN sampling at the time of WT surgery, to maximize surgical disease control. It was proposed that LN density as a metric may allow for improved risk-stratification, and possibly allow for therapeutic reduction in a sub-set of patients with low LN density.

Understanding human dendritic cell biology through gene profiling.

Dendritic cells are potent antigen presenting cells whose function has been associated with a variety of immunological disorders. Because of their relevance to human disease, extensive efforts have been made to gain a better understanding of their biology. One aspect of these efforts has been in the identification of pertinent molecules expressed in these cells through gene profiling experiments and proteomics. In this review, we summarize the results from the various profiling studies that have been done with human dendritic cells. We focus on molecules, which have been confirmed by other methods, such as quantitative PCR, or have been identified in multiple profiling studies to be expressed in the respective dendritic cell type. Through such profiling experiments and subsequent analysis, interesting molecules have been identified which can be further studied to determine their role in dendritic cell biology.

Pyridoxine (vitamin B6) toxicity: enhancement by uremia in rats.

Pyridoxine is not completely innocuous. Large doses can cause a peripheral neuropathy despite renal excretion of this water-soluble vitamin. Renal failure patients are treated with pyridoxine to prevent a deficiency. The safety of pyridoxine treatment in the presence of renal dysfunction has not been studied. Our experiments on anephric rats show that the uremic state, in a mere 3 or 4 days, causes a 5- to 10-fold increase in susceptibility to pyridoxine-induced neuronopathy. These results suggest a need for caution in prescribing pyridoxine to uremic patients who will probably take the vitamin daily for many years.

Proliferation of glial cells induced by lithium in the neural lobe of the rat pituitary is enhanced by dehydration.

Rats dehydrated by 6 days of water deprivation had a low level of mitotic activity in the astrocytes ('pituicytes') of the neural lobe of the pituitary. Mitotic activity in the pituicytes was greatly increased when isotonic lithium was administered in the last 3 days of water deprivation. Rehydration on the last day of the experiment produced a further increase in mitoses. Isotonic solutions of sodium, potassium or rubidium chloride did not increase mitoses. This model of cell proliferation is of interest because the mitotic activity is related to a physiological attempt to maintain homeostasis rather than a response to injury or the development of neoplasia.

Prevention of chronic peritonitis caused by osmotic dysequilibrium in rats.

OBJECTIVE AND DESIGN: This study was done to determine whether peritonitis caused by osmotic dysequilibrium could be prevented by pretreatment. SUBJECTS: Young adult rats were used after induction of peritonitis by intraperitoneal injections of large volumes of pure water to create severe osmotic dysequilibrium. TREATMENT: During the 1 or 2 weeks before induction of peritonitis, the rats were pretreated by intraperitoneal injections of small volumes of pure water or large volumes of moderately hypotonic electrolytes to produce a slight degree of osmotic dysequilibrium. METHODS: Peritonitis was evaluated by macroscopic and microscopic study of peritoneal tissues. RESULTS: The severity of peritonitis was greatly reduced by the pretreatments. CONCLUSIONS: This study adds the peritoneum to the list of tissues in which adaptation to an injury can be accomplished by pretreatment with the same injurious agent, albeit in a less noxious form.

Peritoneal toxicity of water: a model of chronic peritonitis caused by osmotic dysequilibrium in rats.

The purpose of this work was to determine whether the osmotic dysequilibrium created by intraperitoneal (i.p.) injection of pure water has any permanent, damaging toxic sequelae. Rats were injected i.p. with pure water on five successive days. Necropsies were performed 1 week after the last injection. Necropsies revealed fibrosis of peritoneal surfaces of liver and spleen, similar to the effects of chemical irritants but milder. The severity of the lesions depended on the dose of water and the number of injections. A few minutes of contact with pure water was sufficient to ensure subsequent development of fibrosis. Soon after the initial injury, the inoculum became less hypotonic and then isotonic. Isotonic or moderately hypotonic electrolyte solutions did not produce peritoneal fibrosis but very hypotonic solutions were toxic. Injection of the synthetic compound 48/80, which is known to cause discharge of mast cell granules, did not produce peritonitis, nor was contamination by endotoxin or by blood responsible for the lesions. Injection of water may be a useful method for investigating the role, if any, of mast cells and/or mesothelial cells in the toxic effects of osmotic dysequilibrium.

Are urea and creatinine uremic toxins in the rat?

Urea and creatinine are not generally considered to be important uremic toxins despite evidence from dialysis experiments to the contrary, and despite striking elevations of these nitrogenous waste products in uremia. In order to study this problem in acute uremia, we used a new dietary method for prolonging the survival of bilaterally nephrectomized rats. Urea or creatinine were injected on three successive days starting one day after the inception of uremia. Urea or creatinine injections shortened the survival time of acutely uremic rats, and increased the involution of thymus and spleen. The extra urea, but not creatinine, increased the serum osmolality. These data indicate that urea and creatinine are toxic in the acutely uremic rat. Hypertonicity of the serum may contribute to the toxicity of urea. Additional mechanisms of toxicity and additional toxins are not excluded.

Proliferation of glial cells in vivo induced in the neural lobe of the rat pituitary by lithium.

Lithium salts are widely used for treatment of psychiatric illness. Lithium also affects cell proliferation. During investigation of the effect of lithium chloride on the central nervous system (CNS) of nephrectomized rats, we noted numerous mitotic figures in the neural lobe of the pituitary. Morphologic criteria established that the mitotic cells were astrocytes, the supporting glial cells of the CNS, also known as pituicytes. Equimolar doses of chlorides of chemically related cations (sodium, potassium, rubidium) had no such effect.

Feeding sugar overnight maintains metabolic homeostasis in rats and is preferable to overnight starvation.

Rats are often starved overnight for many different reasons. Overnight starvation causes loss of body and liver weights, depletion of liver glycogen, decrease of blood glucose and loss of amino acids because of gluconeogenesis. Providing pure sucrose cubes as the sole overnight nutrient is a simple, inexpensive way to empty the gastrointestinal (GI) tract, while minimizing liver changes and preventing decrease of blood glucose and loss of amino acids. Adding sugars to the overnight drinking water as the sole nutrient has the same beneficial effects, provided the type of sugar and its concentration allow for sufficient intake and provided hyponatremia is avoided. Feeding sucrose cubes or sugar solutions will empty the gastrointestinal tract as effectively as starvation. In all instances, simple precautions against coprophagy and pica should be taken in order to secure optimal benefit.

Pertussis vaccine and pertussis toxin increase lithium levels in rats: possible role of G-proteins.

A single dose of lithium was injected intravenously or intraperitoneally in rats. Lithium levels in serum and tissues 5 or 24 hours later were elevated when the rats were pretreated with pertussis vaccine (PV). The vaccine was effective whether given locally (subcutaneous) or systemically (intravenous). Tests of heated (inactivated) PV suggested that pertussis toxin might be responsible for the effects of PV. Injection of purified pertussis toxin (PT) confirmed this suggestion. Elevation of serum urea nitrogen suggested that lithium levels were increased because the combination of PV or PT with lithium reduced renal excretory function which could cause retention of lithium. Inasmuch as PV and PT are known to inactivate the inhibitory G-proteins, these data suggest G-protein involvement in the elevation of lithium levels by PV and PT.

Repeated toxic injury of peritoneum: accumulation of toxicity and adaptation to injury.

In order to develop new methods for the study of pathogenesis of post-injury fibroplasia, a rat model of chemical peritonitis was explored. Sodium hypochlorite (NaOCl) of various concentrations was injected intraperitoneally one or more times using different intervals between doses. Some time later, the surface fibrosis of liver, spleen, omentum and other abdominal organs was evaluated. A dose-response relation at intermediate concentrations and an apparent threshold at low concentrations were observed. Fibroplasia was increased by repeated doses (accumulation) but it was ameliorated compared to the same total amount of chemical given as a single injection (adaptation during repeated dosing). The rapid disappearance of the chemical irritant and the large size and easy accessibility of the peritoneal cavity suggest that this model may be useful in further study of chemical toxicity and fibroplasia in relation to human fibrosing diseases and injuries (trauma, surgery, peritoneal dialysis). The model has the unique feature of evaluating the morphological effects of the toxic injury and secondary functional effects at the same time.

Ascites produced in rats without tubercle bacilli or tumor cells.

Intraperitoneal injection of rats with two doses of pertussis vaccine produces a small amount of ascitic fluid. Much larger amounts of fluid are produced when two spaced injections of the vaccine are preceded by a small amount of liquid petrolatum. A similar result is obtained by a single injection of pertussis vaccine emulsified in liquid petrolatum and Arlacel A. Ascites produced without tubercle bacilli or tumor cells may increase the use of rats for antibody production.

Transforming growth factor-alpha levels in the serum and ascites of patients with advanced epithelial ovarian cancer.

A variety of cytokines have been identified to play a role in ovarian cancer. In this pilot study, we sought to determine whether transforming growth factor-alpha (TGF-alpha) was detectable in the serum and ascites of women with advanced stage epithelial ovarian cancer. TGF-alpha was measured using an enzyme-linked immunosorbent assay and was present in 18 of 25 control sera. Prior to treatment for stage III or IV epithelial ovarian cancer, 18 patients had undetectable serum levels of TGF-alpha, while 18 had values ranging from 10.6 to 531.7 pg/ml. The group with undetectable levels had a 6-month greater median survival; detectable TGF-alpha might be a negative prognostic indicator. In a separate group undergoing second-look laparotomy, differences in median TGF-alpha values versus controls and the primary study group approached significance. TGF-alpha was detected in significantly more control peritoneal fluid samples than in patient ascites. A larger study is warranted.